Use of N-acetyl-D-glucosamine in the manufacture of pharmaceutical useful for treating motion sickness

ABSTRACT

The present invention has disclosed a use of N-acetyl-D-glucosamine in the manufacture of a medicament for preventing and treating motion sickness, the preparation in which N-acetyl-D-glucosamine is taken as a main active component is able to be used for preventing and treating motion sickness with an effective rate up to more than 90%.

TECHNICAL FIELD

The present invention relates to the use of N-acetyl-D-glucosamine inthe manufacture of a medicament for preventing and treating the motionsickness.

BACKGROUND ART

Motion sickness is a general denomination of carsickness, seasickness,airsickness and a disease caused by swinging, bumping, rotation,accelerated moving and other various factors. The disease often appearsseveral minutes or hours after riding, navigating, flying and othermovements. The patient firstly feels uncomfortable in the upper stomach,then nauseated, looks pale, breaks into a cold sweat; after that,dizziness, mental depression, secreted sputum increase and vomiting mayoccur, and there may be a blood-pressure decrease, irregular breathing,nystagmus. Serious vomiting may cause deprivation of body fluids and adisorder of electrolytes. Generally, the symptom will disappear orlighten several ten minutes or several hours after stopping the motionor decelerating the velocity. There is also a possibility that thepatient can not recover even several days later, and be dispirited, andhave limb asthenia. When the motions or accelerations are repeated, thesymptoms may reappear.

The disease is mainly related to the function of vestibule. Thecysto-ciliary cell of oval vesicle and sphere vesicle of internal earlabyrinth in the vestibule can mainly feel the linear motion up anddown, right and left. The ampullary crest ciliary cell of threesemicircular canals mainly feel the rotation motion. There are manystatic cilia and one dynamic cilium in each ciliary cell, the cilia arecovered with colloidal membrane consisting of glycoprotein,mucopolysaccharide. The colloidal membrane (anpullae cap, statolithicmembrane) can interact with cilia to form a location sensor. Whenstarting or stopping the rotation or linear motion, the displacement ofinner lymph will lead to the displacement of the colloid membrane, soapplying stimulation to the cilia, and the excitation caused by ciliarycell is passed into cerebra through the vestibular nerve. The ciliaryswing of normal person's ciliary cell is in a chaos rhythm, which isvery easy to couple and adapt with a random stimulation caused byoutside motion. But the ciliary swing of the ciliary cell of a patientsuffering from motion sickness is in a quasi-periodicity, so it isdifficult to couple with the random stimulation caused by outsidemotion, leading to a continuous excitation of the ciliary cell, which istransferred from the vestibular nerve to the vestibular nerval nucleus,then transferred to the cerebellum and hypothalamus in proper order,causing a series of clinical symptoms. The stimulation to vestibular mayaffect the structure of the network, induce the reduction of bloodpressure and vomiting. Vestibular nerval nucleus may cause nystagmusfrom the medial longitudinal fiber to eye muscle motor nuclei; after thecerebellum and hypothalamus suffer from nerval impulse, the change ofthe muscular tension all over the body will occur. The stimulation tocerebellum may also be another mechanism of this disease.

At present, there is not an effective way for preventing and treatingmotion sickness. The pending solutions mainly use anti-histamine agentsand belladonna agents, or an anti-vomiting agent (metoclopramide), orsedative (such as phenobarbital). These medicaments have large sideeffects, and bring many inconveniences to trips and to living.

CONTENTS OF THE INVENTION

The object of the present invention is to provide a new method andmedicament for preventing and treating motion sickness disease.

The applicant of the present invention has surprisingly found thatN-acetyl-Dglucosamine and pharmaceutical acceptable salts thereof areable to effectively prevent and cure motion sickness disease. BecauseN-acetyl-Dglucosamine has no toxicity, and have a unique curativeeffect, without influence on the trip and living, it can be used widelyfor a long period.

Therefore, the present invention is related to a method for preventingand treating the motion sickness, including administering to a patientwho is in need thereof of an effective amount of N-acetyl-D glucosamineand pharmaceutical acceptable salts thereof.

On the other hand, the present invention is related to the use ofN-acetyl-D-glucosamine and pharmaceutical acceptable salts thereof inthe manufacture of a medicament for preventing and treating motionsickness disease.

In the research of “bio-waves” theory, the present inventor has set up abacterial wave growth model. Through research, it is known that thiswave is of its intrinsic regulation mechanism: some chemical substancesare able to participate in regulation in the bio-wave process, so as totransform an abnormal periodic slow wave into a normal physiologicalchaotic quick wave, and these kinds of substances are known as promotingwave factors. Through separating, purifying and identifying, it isdetermined that one of the factors is N-acetyl-D-glucosamine, thepromoting wave function of which is shown in lubricating and protectingthe cell. Many biochemical and physiological processes of the human bodyneed the participation of the promoting wave factors, and it would leadto an abnormal state, if this kind of promoting wave factors is missingin the living body.

The structure of N-acetyl-D-glucosamine is as follows:

N-acetyl-D-glucosamine can be purchased in the market or preparedaccording to known methods. For instance, patent application WO97/31121has disclosed a method for preparing N-acetyl-D-glucosamine from chitinby enzyme method, Japanese patent application JP63273493 has disclosed amethod in which chitin is partially hydrolyzed into N-acetyl-chitose,and then it is treated with enzyme to obtain N-acetyl-D-glucosamine.

The pharmaceutical acceptable salts of N-acetyl-D-glucosamine that canbe mentioned are the salts formed with pharmaceutical acceptable acids,for instance, the salts formed with inorganic acids, such ashydrochloride, hydrobromide, borate, phosphate, sulfate sulfite andhydrophosphate, and the salts formed with organic acids, such ascitrate, benzoate, ascorbate, methyl sulfate, naphthalene-2-sulfonate,picrate, fumarate, maleate, malonate, oxalate, succinate, acetate,tartrate, mesylate, tosylate, isethionate, α-ketoglutarate, α-glycerylphosphate and glucose-1-phosphate.

N-acetyl-D-glucosamine is a chemical reagent. From the 1990's, it iscontinually used to treat pericementitis (WO9102530A1), microbiologicalinfection (WO9718790A3), intestinal inflammation (WO9953929A1), corneadisease (JP10287570A2), hypertrophy of the prostate (U.S. Pat. No.5,116,615) and so on. It is also applied in cosmetology (JP59013708A2),shampoo preparation (JP2011505A2), tissue growth regulation agent (WO/A8 702244), and etc., but it has not been used in the manufacture of amedicament for preventing and treating motion sickness.

The applicant of the present invention has found thatN-acetyl-D-glucosamine is able to effectively prevent and treat motionsickness. Because its toxicity and side effects are very light, usingN-acetyl-D-glucosamine to prevent and treat motion sickness may avoidundesired side effects caused by current medicaments for preventing andtreating the disease. Depending upon the necessity, a small dosage for along term treatment or a large dosage for a short term treatment can beadopted.

For the purpose of treating the motion sickness disease,N-acetyl-D-glucosamine can be used alone or used in the form of apharmaceutical preparation made by combining with pharmaceuticalacceptable excipients or/and carriers. This kind of preparation can bein any form for convenient traditional administrations. Preferably, thepreparations are in the form of liquid or solid for oral administration.A conventional method can be used to prepare the medical compositions inthe form of suitable pharmaceutical preparations, for instance mixing,granulating, tableting, sugar coating, film coating and so on. Theliquid preparations for oral administration may use aseptic water andaseptic saline solution as carriers, and alcoholic drinks like alcoholsmay also be taken used as carriers. In a preferred embodiment, theconcentration of N-acetyl-D-glucosamine in alcoholic drink is 0.1˜4% byweight. For a solid preparation such as a tablet or capsule, in additionto the compound of formula (I), it may also include diluent, such aslactose, glucose, cellulose, starch, lubricant such as silica, talc,magnesium stearate or calcium stearate, and/or polyglycol; binder suchas starch, Arabic gum, methyl cellulose, carboxymethyl cellulose,polyvinylpyrrolidone; depolymerizing agent such as starch, alginic acid,aliginate, starch sodium glycolate; foaming mixture; colorant;sweetener; lubricant such as lecithin, polyethenoxy ether and so on.

Preferably, said medicament is administrated to the patients in needthereof orally with a dosage of 1000˜10000 mg of N-acetyl-D-glucosaminedaily in the period from 2˜3 days before the trip to the end of thetrip, wherein the trip is by car, navigation or flying, for preventingand treating motion sickness disease in a short period.

In the same way, preferably, said medicament is administrated to thepatients in need thereof orally with a dosage of 200˜2000 mg ofN-acetyl-D-glucosamine daily, for preventing and treating motionsickness disease in a long period.

More preferably, the medicament with alcoholic drink as carrier isadministrated to the patient in need thereof orally with a dosage of200˜1000 mg of N-acetyl-D-glucosamine daily in the period from 2˜3 daysbefore the trip to the end of the trip, wherein the trip is by car,navigation or flying.

Though having no intention to be limited to any theory, the applicantthinks that motion sickness is substantially a disease caused by losingcoupling due to oscillation. As a regulating factor of the bio-waves,N-acetyl-D-glucosamine possesses a wide regulating function to thebio-waves. Through the following three aspects, it is able to developits special effect in preventing and treating the motion sickness:

(1) Regulating the rhythmical wave of the cilia in the internal earciliary cell. The swinging of ciliary cluster in the ciliary cell is inrhythm, and can be regulated. But N-acetyl-D-glucosamine is able toregulate the quasi-periodic wave of the cilia swing of the ciliary cellof the patient to form a chaos wave, so as to make it easy to couplewith outside random rhythm and raise adaptive ability of the patient tothe outside motion.

(2) Regulating the viscosity of ampullae cap and statolithic membrane.Ampullae cap and statolithic membrane are both colloidal membranesformed by glycoprotein as a main component, which transfer the motion ofthe outside world so as to produce an action to the cilia of ciliarycell, N-acetyl-D-glucosamine is a precursor substance of glycoprotein,which can promote the ciliary cell to secrete glycoprotein so as toraise the viscosity of the colloid membrane. Increasing viscosity willstrengthen the coupling between colloid membrane and cilia, favorable tothe coupling between the swing of cilia and outside motion.

(3) Regulating the excitation of vegetative nerve and vestibule nerve.N-acetyl-D-glucosamine is able to regulate the waves of the nerval celland network thereof. The continuous single wave transferred from ciliarycell to vestibule nerve, cerebellum, hypothalami and vegetative nerve isregulated into a shape-separating chaos wave. After subjecting todisturbance, the movement of vegetative nerve and vagus nerve also tendsto an absorbed point so as to relieve or remove nauseating, vomiting,paleness cold sweats, dizziness, decreased blood pressure, nystagmus andso on.

OPTIMAL MODE FOR CARRYING OUT THE INVENTION

The following experimental examples are used to illustrate the promotingwave function, low toxicity, and the effect for preventing and treatingmotion sickness disease, of N-acetyl-D-glucosamine (NAG).

I. Promoting Wave Test of N-acetyl-D-glucosamine

1. Experimental Materials and Method:

1.1 Samples: Pure Compound of Formula (I)

1.2 Experimental Materials:

-   -   Strain: Proteus Mirabilis (which should comply with the        following biological reaction characteristics: dynamics (+),        urease (+), lactose (−), glucose (+), H₂S (−), phenylalanine        deaminase (+).    -   Culture medium: modified LB culture medium (the components of        the composition are: trytones of 1%, yeast extract of 0.5%,        sodium chloride 1%, glucose of 0.1%, TTC of 0.002% and        pH=7.2˜7.4).

1.3 Experimental Method:

-   -   The Proteus Mirabilis were inoculated at the center of LB plate,        incubating at 37° C. for 9 hours, then there were concentric        rings emerged, which were extended outward continually with an        interval of 3 hours, and this was taken as a control; adding the        compound of formula (I) with final concentration of 0.5% onto        the LB plate, The Proteus Mirabilis were innoculated by the same        method, cultured at 37° C., and the result showed that not only        the concentric rings formed with an interval of 3 hours were        emerged, comparing with the control, it can be seen that there        were also many fine waves on each ring emerged.        2. Experimental Results and Evaluation:    -   The experiment adopts a bio-wave model which is used to research        the promoting wave function of N-acetyl-D-glucosamine. It can be        seen from the results that the compound of formula (I) was not        only able to cause bacterial cell to reveal a normal bio-wave        characteristic, but also to cause the wave to reveal a finer        wave mode, and these indicated that N-acetyl-D-glucosamine have        promoting function to bio-waves, and the promoting wave function        is able to participate in the coupling oscillation waving        procedure conducted by inner ear ciliary cell and nerve system.        II. Toxicological Test of the Compound of Formula (I),        including:

1. acute toxicity test: including tests of administrating medicine byoral, Intravenous injection and maximum limit amount for administration;

2. Ames test;

3. micronucleus test of bone marrow cell of mouse;

4. abnormal sexual test for the sperm of mouse;

5. abnormal aberrance test for the chromosin of mouse's testis;

6. chronic lethal test;

7. subchronic toxicity (feed for 90 days) test;

8. traditional aberrance-inducing test;

-   -   The results from these tests show that in the acute toxicity        test of the compound of formula (I), a dosage of more than 2        g/kg is taken, which is 300 times greater than the injection        dosage for human being, but the acute toxicosis reaction had not        appeared yet. In the long-period toxicity test, the maximum        dosage has reached up to 1 g/kg, and after the treatment and        observation for four weeks, there is no toxicosis reaction yet;        and in the reproduction test, the mouse was fed with routine        dosages from 7 mg/kg for 3 generations, and it has been proved        that the compound of formula (I) has no influence on the        pregnancy, birth, nursing and the growth of baby mice. So it is        proved that the compound of formula (I) is a substance without        toxicity.        III. Observation of Curative Efficiency.

80 patients suffering from motion sickness were selected and randomlydivided into four groups: a group to whom N-acetyl-D-glucosamine wasadministered in a long term (800 mg of NAG/person/day), a group to whomN-acetyl-D-glucosamine was administered in a short term (6000 mg ofNAG/person/day), placebo group (6000 mg of glucose/person/day), a groupto whom no medicament was administered. A double blind method wasadopted, observing the curative efficiency for traveling 100 kilometersby car (its velocity was 20 kilometers/hour) and traveling 100kilometers by a small steamboat. Compared with the situation beforetraveling by car, the following symptoms being relieved or removed willbe judged to be effective: dizziness, nausea and vomiting. The resultscan be seen from the following table:

Number of person Effective Not effective NAG long term group 20 18 2 NAGshort term group 20 19 1 Placebo group 20 3 17 No administration 20 2 18

As shown in the table, the statistic results indicate that theeffectivity of preventing and treating motion sickness withN-acetyl-D-glucosamine is more than 90%, remarkably different from theplacebo group and the group to which the medicament was not administered(p<0.05).

1. A method of treating a subject who has been or who will be subjectedto movements that can cause motion sickness, the method comprisingadministering to the subject an effective amount of a medicamentcomprising N-acetyl-D-glucosamine and/or a pharmaceutically acceptablesalt thereof in an amount effective to prevent or to relieve symptoms ofmotion sickness.
 2. The method according to claim 1, wherein saidmedicament is administrated to the subject orally in form of an oralsolution or a solid preparation.
 3. The method according to claim 2,wherein said medicament is administered to the subject in an alcoholicdrink containing 0.1˜4% by weight of N-acetyl-D-glucosamine and/orpharmaceutically acceptable salts thereof.
 4. The method according toclaim 1, wherein said medicament is administered to the subject in needthereof orally with a dosage of 1,000˜10,000 mg ofN-acetyl-D-glucosamine and/or a pharmaceutically acceptable salt thereoffrom 2˜3 days before the trip to the end of the trip, wherein the tripis by car, navigation, or flying, for preventing or relieving thesymptoms of motion sickness.
 5. The method according to claim 1, whereinsaid medicament is administered to the subject in need thereof orallywith a dosage of 200˜2,000 mg N-acetyl-D-glucosamine and/or apharmaceutically acceptable salt thereof daily for preventing orrelieving the symptoms of motion sickness for a period exceeding 3 days.6. The method according to claim 3, wherein said medicament isadministrated to the subject in need thereof orally with a dosage of200˜1000 mg of N-acetyl-D-glucosamine and/or pharmaceutically acceptablesalts thereof daily from 2˜3 days before the trip to the end of thetrip, wherein the trip is by car, navigation or flying.
 7. The methodaccording to claim 1, wherein the symptoms are selected from the groupconsisting of dizziness, nausea and vomiting.
 8. The method according toclaim 7, wherein the medicament is administered to the subject prior tothe subject being subjected to movement that can cause motion sickness.